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LORBRENA®Drug Interactions (lorlatinib)

7 DRUG INTERACTIONS

7.1 Effect of Other Drugs on LORBRENA

Effect of CYP3A Inducers

Concomitant use of LORBRENA with a strong CYP3A inducer decreased lorlatinib plasma concentrations, which may decrease the efficacy of LORBRENA. The effect of concomitant use of LORBRENA with a moderate CYP3A inducer on lorlatinib plasma concentrations has not been studied.

Severe hepatotoxicity occurred in healthy subjects receiving LORBRENA with rifampin, a strong CYP3A inducer. In 12 healthy subjects receiving a single 100 mg dose of LORBRENA with multiple daily doses of rifampin, Grade 3 or 4 increases in ALT or AST occurred in 83% of subjects and Grade 2 increases in ALT or AST occurred in 8%. A possible mechanism for hepatotoxicity is through activation of the pregnane X receptor (PXR) by LORBRENA and rifampin, which are both PXR agonists. The risk of hepatotoxicity with concomitant use of LORBRENA and moderate CYP3A inducers that are also PXR agonists is unknown.

LORBRENA is contraindicated in patients taking strong CYP3A inducers. Discontinue strong CYP3A inducers for 3 plasma half-lives of the strong CYP3A inducer prior to initiating LORBRENA.

Avoid concomitant use of LORBRENA with moderate CYP3A inducers. If concomitant use of moderate CYP3A inducers cannot be avoided, monitor ALT, AST, and bilirubin as recommended [see Dosage and Administration (2.3), Warnings and Precautions (5.1), Clinical Pharmacology (12.3)].

Effect of Strong CYP3A Inhibitors

Concomitant use with a strong CYP3A inhibitor increased lorlatinib plasma concentrations, which may increase the incidence and severity of adverse reactions of LORBRENA. Avoid the concomitant use of LORBRENA with a strong CYP3A inhibitor. If concomitant use cannot be avoided, reduce LORBRENA dose as recommended [see Dosage and Administration (2.4), Clinical Pharmacology (12.3)].

7.2 Effect of LORBRENA on Other Drugs

CYP3A Substrates

Concomitant use of LORBRENA decreases the concentration of CYP3A substrates [see Clinical Pharmacology (12.3)], which may reduce the efficacy of these substrates. LORBRENA is considered a moderate CYP3A inducer. Avoid concomitant use of LORBRENA with CYP3A substrates, for which minimal concentration changes may lead to serious therapeutic failures. If concomitant use is unavoidable, increase the CYP3A substrate dosage in accordance with approved product labeling.

P-glycoprotein (P-gp) Substrates

Concomitant use of LORBRENA decreases the concentration of P-gp substrates [see Clinical Pharmacology (12.3)], which may reduce the efficacy of these substrates. LORBRENA is considered a moderate P-gp inducer. Avoid concomitant use of LORBRENA with P-gp substrates for which minimal concentration changes may lead to serious therapeutic failures. If concomitant use is unavoidable, increase the P-gp substrate dosage in accordance with approved product labeling.

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